Is SMPD4 p.Arg331Pro (c.992G>C) pathogenic?

SMPD4 p.Arg331Pro (c.992G>C) is classified Uncertain significance in SMPD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.9963); Very rare (popmax 0.00306%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SMPD4 p.Arg331Pro (c.992G>C)?

SMPD4 p.Arg331Pro (c.992G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SMPD4 p.Arg331Pro (c.992G>C) in the general population?

SMPD4 p.Arg331Pro (c.992G>C) is very rare (popmax 0.00306%, nfe) (gnomAD).

What do computational predictors say about SMPD4 p.Arg331Pro (c.992G>C)?

AlphaMissense predicts likely pathogenic (score 0.9963) — an in-silico prediction, not a clinical call.

SMPD4 p.Arg331Pro

c.992G>C · VCV3446445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9963	likely pathogenic · top 1% in SMPD4
REVEL	0.481	indeterminate
SaProt	LLR -14.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 733 bp · p 8.9e-07 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R370P vs ClinVar R331P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% European (non-Finnish) · 36/1,176,236 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00224% 36/1,603,598 alleles · very rare exomes 35/1,451,518 · genomes 1/152,080 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SMPD4
Protein: p.Arg331Pro
Coding: c.992G>C
MANE Select: NM_017951
Type: single nucleotide variant
Location: chr2:130157356 (GRCh38)
Gene constraint: LOEUF 0.769 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.01
Residue 370 UniProt numbering: a UniProt-annotated variant site (in nedmaba)

Full SMPD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMPD4 p.Arg757Trp Uncertain significance ★★ ⚠ same condition
SMPD4 p.Gln382Glu Uncertain significance ★★ ⚠ same condition
SMPD4 p.Ile82Val Uncertain significance ★★ ⚠ same condition
SMPD4 c.-105G>A Uncertain significance ★ ⚠ same condition
SMPD4 c.-11T>C Uncertain significance ★ ⚠ same condition
SMPD4 c.-52C>G Uncertain significance ★ ⚠ same condition
SMPD4 c.-57T>C Uncertain significance ★ ⚠ same condition
SMPD4 p.Ala252Thr Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/smpd4-p-arg331pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown